J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from Journal ofNeurology, Neurosurgery, and Psychiatry, 1972, 35, 711-719

Neurological abnormalities in the 'cri-du-chat' syndrome1

JACK COLOVER, MARY LUCAS, J. A. COMLEY2, AND A. M. ROE2 From the South-East Metropolitan Regional Neurological Unit, Brook General Hospital, London, S.E.18, and Galton Laboratory, University College, London, W.C.]

SUMMARY An unusual case of the cri-du-chat syndrome is described in a 61 year old boy, who, as well as attacks of stridor and choking, showed disorders of spatial perception and cerebellar signs in the form of nystagmus, clumsiness of the hands, and ataxia. Pyramidal signs were also present. He was only mildly retarded mentally. Psychological testing showed that he had a severe deficit for number processing, and also constructional apraxia. Surprisingly, his vocabulary was quite good, as was his reading capacity. Chromosome analysis showed a very small deletion of the short arm of the group B chromosome. In infancy this diagnosis may be suspected because of the high-pitched cry and attacks of stridor and choking. In late childhood, when the signs may be only of a neurological disorder, its recognition may be difficult without confirmation from chromosome studies. The are neurological features of this disease reviewed. Protected by copyright.

The cri-du-chat syndrome was first recognized by child a very alert appearance; premature greying Lejeune, Lafourcade, Berger, Vialatte, Boeswill- of the hair; acyanotic heart disease. wald, Seringe, and Turpin (1963). Females are The details of the neurological conditions more prone to it than males, the relative inci- found will be described in more detail below. dence being about 2 to 1. About 100 cases have been described (Polani, 1969). Practically every CASE REPORT patient has been noted to have an abnormal cry in infancy and this has been likened to the cry of The proband was referred by his own doctor in 1969, a cat or kitten. It has also been described as at the age of 6- years. He was the second of three in children, the other two being normal. The father was sounding like a seagull distress. As the child normal. The mother was a nurse and was able to give gets older the abnormal cry may be lost. One a good account of his past history. The parents were child when sneezing made a noise like a crow, unrelated. Detailed records were available from an

and also suffered from hiccups (Turner, Bass, early age. http://jnnp.bmj.com/ and Kaplan, 1966). When the mother was two months pregnant she The following features are commonly found: had been exposed to German measles and had re- microcephaly; gross mental retardation and ceived gamma globulin. The delivery was normal at full term and the birth weight was 3-6 kg (7 lb 15 oz). motor retardation; physical retardation and At birth his mother noted that he had a triangular- failure to thrive; hypertelorism; epicanthic folds; shaped head. He was breast-fed for three weeks. downward slant to the palpebral fissures-anti- When bottle feeding was started it was found to be

mongolism; strabismus, the incidence of this is difficult and he vomited occasionally. The vomit on September 28, 2021 by guest. very high indeed. always contained much mucus. He always had a Less common features are the following: the high-pitched cry. His father said his cry was like corneae be the that of a Siamese cat. Weight gain was slow but may abnormally large-giving steady. His developmental milestones were a little delayed. 1 Based on a paper read to the Association of British Neurologists did on 21 November, 1970. He not smile until he was 10 weeks old and he 2 From the Department of Education, London Borough of Bexley. developed head control at 4 months. There was a 711 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from 712 Jack Colover, Mary Lucas, J. A. Comley, and A. 14. Roe history of a single bout of diarrhoea with passage of shrill cry and he cried like a cat. The difficulties with pale loose bulky stools. his feeding persisted. He was examined at the age of 1 year when he was A report on him at the age of 3 years stated that he found to be fair-haired and blue-eyed. The skull often suffered from abdominal colic. He screamed was asymmetrical and head circumference was 40 cm constantly and took only small amounts of food. He (177 in). He was able to sit momentarily. He was ad- did not sit up till the age of 16 months and he was mitted to hospital at that age for 10 days and while nearly 2 years old before he stood up-but he walked there was found to be a happy child who often made soon after. At the age of 2{ years he had started to odd clucking noises. He was a poor feeder but this speak. He was reported as being very fidgety when was attributed to mental retardation. Limb move- aged 3. Also he was easily upset and very tense. He ments at times appeared abnormal and were observed was thought to have some nervous spasm of the to be athetotic. His respirations were always noisy. bowel associated with excessive aerophagy. He did He vomited occasionally and there was much mucus not give the impression of being very backward. in the vomit. There was marked facial and skull In his past history he had had measles, otitis asymmetry. The nasopharynx contained much media, and mumps. He had received triple vaccine, watery mucus and over the upper respiratory tract polio vaccination, and a booster injection. It had transmitted noises could be heard. Radiographs of been noted that he had a lazy right eye. his chest showed an enlarged thymus gland. At the age of 6} years the difficulties with his At the age of 18 months he had stridor. He fre- feeding had persisted and he still choked over his quently choked over his food and had a hoarse cry. food. He was quite continent, was clean in his habits, The neighbours had commented that he had a very and had learned to dress himself. He was allergic to Protected by copyright.

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FIG. 1. Frontal view ofpatient. FIG. 2. Lateral view ofpatient. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from Neurological abnormalities in the 'cri-du-chat' syndrome 713 wasp stings. The mother repeatedly mentioned that husky. There was nystagmus when he looked to the right from birth he had an odd cry and on one occa- right and he showed a slight squint. His arms were sion used the words 'he sounded like a strangled hypotonic and there was ataxia of the lower limbs cat'. His voice was husky and he still had a hoarse and intention tremor of the left hand. The left plantar cry. He dropped objects that he was holding. His response was extensor. His handwriting was odd and balance was poor and he dithered on stairs. he wrote his name in a curious pattern. On examination at that age it was noted that he Mr. A. E. Howarth (consultant ENT surgeon) looked very alert (Figs 1 and 2). His voice was obtained the history that he often became cyanosed

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FIG. 3. Chromosome pattern showing deletion of short arm of one chromosome, No. 5. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from 714 Jack Colover, Mary Lucas, J. A. Comley, and A. M. Roe and choked over his food. There had been six attacks recently. He still had a cry like a cat occasionally at night. There was a history of repeated colds. He was admitted for laryngoscopy and found to XI be somewhat wheezy. Under anaesthesia it was found iI 'T that his epiglottis was normal. The larynx was appar- J .1 ently normal when paralysed with scoline but when he was recovering it was seen that there was asym- metry of the larynx, with the right arytenoid lying forward, and there was no movement of the right vocal cord. Oesophagoscopy was normal. ,

LABORATORY AND RADIOLOGICAL INVESTIGATION At 4 the age of year blood examination showed 1 (two iL estimations) haemoglobin levels of 72% and 68%,, with a normal total white cell and differential count (7,700/c. mm). Urinary aminoacid pattern was thought to be at the upper limit of normal on one occasion, and on another occasion slightly raised levels of serine, A glutamine, alanine, glycine, and histidine. Serum proteins were normal. His blood count showed 11 5 g haemoglobin/100 ml. with 10,000 white cells per c. mm and normal leucocytes and platelets. The sedi- U mentation rate was 26 mm (Wintrobe). The serum Protected by copyright. glucose when fasting was normal (70 mg/100 ml.). The CSF protein was 48 mg/100 ml. with a slight increase of globulin but the specimen was slightly bloodstained. The CSF glucose was normal. An EEG at the age of 1 year showed moderate asymmetry between the activities in the frontocentral r regions but no definite paroxysmal features. A pneumoencephalogram at the age of 6+ years 18 showed good filling of all components of the ventri- cular system, which were normal in situation, but the left lateral ventricle showed slight rounding of the angle, indicating slight enlargement of the ventricle. Chromosome studies were undertaken when this patient was aged 61 years. Metaphases from a peri- pheral blood culture were examined and the number of chromosomes was found to be the normal 46. http://jnnp.bmj.com/ The sex chromosomes were XY, the normal male 51i configuration. Very careful examination showed that there was an abnormality in group B: chromosomes nos. 4 and 5, Denver system. One of these showed a very small deletion of the short arms (Fig. 3). This was more obvious in some cells than others (Fig. 4). The chromosome preparations were sent to Dr.

Jacobs at the Medical Research Council's Clinical X ;I on September 28, 2021 by guest. and Population Cytogenetics Research Unit, Edin- burgh, and she confirmed this finding. Her report reads, 'three independent observers all agree that he 4 1 has a deleted group B chromosome (46XY, Bp-). However we all agree that the amount of deleted material is really very small'. FIG. 4. Pairs of chromosomes. Numbers 4 and 5 Chromosome pairs nos. 4 and 5 cannot be dis- show deletion of one chromosome, No. 5. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from Neurological abnormalities in the 'cri-du-chat' syndrome 715 tinguished morphologically, but they can be differen- He had great difficulty in number processing and this tiated by autoradiography using a radioactive DNA is discussed later: on the two subtest scores with precursor. In this way it has been shown (Miller, greatest discrimination however he scored at a near- Breg, Warburton, Miller, Firschein, and Hirschhorn, average level. On the Performance Scale his poorest 1966) that patients with the cri-du-chat syndrome results were on the Block Design and Object Assem- have a deletion ol chromosome no. 5. There are a bly items and may fairly be labelled as constructional very few cases with a different and more severe spec- apraxia. He was unable to attempt the simplest items trum of congenital abnormalities who also have a on the Book Form of Raven's Coloured Progressive similar deletion. In some of these cases autoradio- Matrices, becoming distressed and tearful when con- graphy has been carried out and the abnormal fronted with the first page. chromosome has been shown to be a no. 4 (Wolf, Reinwein, Porsch, Schroter, and Baitsch, 1965; Taylor, As this did not the Mathematics He showed both clinically and at 1970). patient have gross school a particular malformations described in cases of a deleted no. 4, incapacity to deal with number had a problems. A few ad hoc tests were carried out with and history of the 'cat-cry', the abnormal the aid of chromosome has been placed as a no. 5. It was not materials available in the room (Fogel- to his cells mann, 1970). A jug, water, and a few cups were used possible examine autoradiographically. to test his Some cases of cri-du-chat syndrome are known to ideas of 'conservation of quantity' but he firmly rejected this and treated attempts to change be due to a familial balanced translocation (Lejeune, his mind about it 1965; Laurent and Robert, 1966) in which case there with some hilarity. This would sug- is a risk of another abnormal child being born in the gest that his conceptual development is as yet at family. Therefore blood cultures from the patient's Piaget's first stage. parents were examined. Both Cuisenaire rods were used in an attempt to see showed normal karyo- whether he was able to types; these findings were also confirmed by Dr. size-order a series but he was Jacobs. quite unable to do this, even when a model was Protected by copyright. placed before him and helpful suggestions were made. He had a rudimentary schema of seriation for PSYCHOLOGICAL STATUS He was assessed on several he usually managed to arrange the rods so that seria- occasions between the ages of 61 and 71 years. As no tion was complete for each group of three, another information concerning specific difficulties was avail- series being commenced once he had placed three able to the two psychologists who assessed him, the rods in serial order. His mathematical notions were initial assessments were 'blind'. Detailed psycho- at the level of a 5 to 6 year old child and it was con- metric studies of spatio-motor, cognitive, and lan- sidered that his difficulties in mathematics would guage abilities were embarked upon, as his appear- repay further studies at a later age. ance and gait were so unusual. Assessments scores on the Wechsler Intelligence Scale (WISC), the English Picture Vocabulary Test, the Bender-Gestalt Visuo- Visual perception and motor control When first Motor Test, the Frostig Developmental Tests of examined at the age of 64 years (September, 1969) Visual Perception, and the Illinois Test of Psycho- he was asked to complete the Bender-Gestalt Visuo- linguistic Abilities (ITPA), were done. They yielded Motor Test (Fig. 5). It proved quite impossible to a most unusual and interesting proffile. score the drawings; indeed, it was very difficult to

identify each protocol with the original model http://jnnp.bmj.com/ Intelligence It is usually misleading to quote a (Fig. 6). deviation intelligence quotient without qualification. The Bender-Gestalt Test, although affected by He was initially reported by a local authority phy- both receptive and expressive disorders, fails to dis- sician to show a Binet IQ of 91. About a year later, tinguish usefully between them: on a second occa- on the WISC, his scores were significantly lower than sion, therefore, he was asked to trace the drawings this (V IQ 75, P IQ 87: full scale score 78). Children as they are reproduced in Zazzo (1960) (Fig. 7). This showing signs of visuomotor disturbance commonly time his drawings, although poor, were of a far manifest a large verbal performance discrepancy higher quality. This suggests that his main difficulty on September 28, 2021 by guest. (Abercrombie, 1964; Langan, 1970) and, as his open- was in holding a short-term visual memory trace. field language handling and vocabulary appeared to The Marianne Frostig Developmental Test con- be quite sophisticated, the poor verbal score was firmed the suggestion that his difficulties were recep- rather surprising. There was a great deal of subtest tive rather than expressive: his hand-eye coordina- scatter of 13 points on the full scale WISC and the tion was shown to be poor, but major disabilities very poor achievement in the arithmetic subtest were observed in the Scale subtests which purport to pulled the verbal subscale down very considerably. assess receptive rather than expressive functions. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from 716 Jack Colover, Mary Lucas, J. A. Comley, and A. M. Roe

Illinois Test of Psycholinguistic Abilities This pa- tient was assessed on the ITPA in September 1970- the final testing of the series. He was then aged 7 years 6 months. The norms provided by Kirk, McCarthy, and Kirk (1968) suggest that his mean score was 1-3 standard deviation below the popula- 0 0 0 0 0 0 0 0 0 0 0 tion mean: this is roughly the kind of result which 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 0 0 0 o would be consonant with a global IQ of 80 on a standard cognitive test with a mean of 100 and stan- dard deviation of 15. This is very close indeed to the WISC full scale score of 78 obtained a year earlier and probably represents the level of intelligence he is able to mobilize at present. The pattern of his sub- test scores was of considerable interest; when rank- ordered, from highest to lowest, they ran as follows: Auditory reception 43 Auditory memory 38 Grammatic closure 37 Auditory association 34 (manual expression) Verbal expression 26 Visual reception 26 Visual memory 24

Visual association 22 Protected by copyright. FIG. 5. Bender Gestalt Visuo-Motor Test (after Visual closure 20 Zazzo, 1960). Normal score = 40

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FIG. 6. Copy ofFig. 5 by patient. FIG. 7. Tracing of Fig. 5 by patient. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from Neurological abnormalities in the 'cri-du-chat' syndrome 717

This confirmed the earlier impression that tasks 100,000, or even less, live births. The oldest case concerned with verbal behaviour were handled much described, aged 33 years, is that of Berg, Del- better than those concerned with visual material. hanty, Faunch, and Ridler (1965). Miller, War- The four visual tests had a mean standard score of burton, and Breg (1969) referred to 13 cases over 23-just over two standard deviations below the the age of 12 and to one aged 55 years (in course population mean and roughly equivalent to a WISC score of 68. This was about the same as the general of publication). 'perceptual quotient' obtained a year earlier on the In a series of 55 cases reviewed by McGavin, Frostig Test. The five explicit language tests had a Cant, Ferguson Smith, and Ellis (1967) 39 had mean standard score of 35-6, which was very close the typical cri-du-chat. In another series of 18 to the population mean and equivalent to a WISC cases reviewed by Berg et al. (1965) 16 had the score of IQ 94. It may be concluded that this patient typical cri-du-chat and one was doubtful. Atten- was most severely handicapped in the visual modality tion has been drawn to the fact that in older -and within that modality, in the receptive sphere- patients the cri-du-chat may be absent (Ricci, but that he was near the average in the understanding Ventimiglia, Dallapiccola, Franceschini, and and use of language. It is true that his earlier WISC Preto (1965), and this may make the diagnosis verbal score suggested that his verbal abilities were on clinical grounds quite significantly lower than this; but his specifically very difficult if not impossible poor arithmetic test results contributed to this low in older children or adults. figure and the other subtests on which he did poorly Some authors have not found any abnor- (information and comprehension) appeared to mea- mality in the larynx, but a leading article in the sure, at that stage, general know-how rather than Lancet (1965) mentioned a soft mobile epiglottis verbal ability per se. and underdevelopment of the larynx as being It should be noted that despite these perceptual responsible for the cri-du-chat. Zellweger (1966) handicaps this patient was now reading fluently. described indrawing of the arytenoids and the Protected by copyright. If we accept that there is a sharp bifurcation be- epiglottis. Structural changes in the larynx or tween levels of functioning it is also interesting to sublaryngeal zone were described in De Grou- note that within each modality the rank order of sub- tests was roughly similar. In the auditory-grammatic chy, Arthus, Salmon, Lamy, and Thieffry (1964) subtests the order was: Reception, Memory, Closure, and Lejeune, Lafourcade, De Grouchy, Berger, Association, Expression; in the visual subtests it was: Gautier, Salmon, and Turpin (1964a) and other Reception, Memory, Association, Closure (Manual authors. expression does not clearly belong to either domain). The case described in this paper showed no In terms of Osgood's model (1963) the pattern is structural changes but had paralysis of one vocal suggestive, although of course for a single case it cord. The attacks of choking, which are very cannot reach statistical significance. common, and also the high-pitched cry, suggest that there is a neurological abnormality of Educational prognosis It should be noted that this laryngeal function. It would appear that there is patient had made reasonably good progress in writ- in ing and reading skills despite primafacie evidence of probably some neuromuscular incoordination and the earlier the act of swallowing which causes choking, and perceptual handicaps, suggestions http://jnnp.bmj.com/ (McCracken and Gordon, 1965) that 'severe sub- it is considered more than probable that a similar normality' was a usual concomitant of this condition incoordination is responsible for the cri-du-chat -the cri-du-chat syndrome. Certainly cognitive and in many of these patients. perceptual handicaps were present, yet in spite of Regarding the neuropathological changes, this the patient was holding his own in a class in a there are very few post mortem descriptions. normal state school designed for children of low Solitare (1967) described a 19 year old girl who general ability. His vocabulary, reading, and general died with this condition and he considered that language handling were not good, but they were con- she had a miniature brain but that its cyto- on September 28, 2021 by guest. siderably better than for many so-called 'normal' children. architecture was normal. This is a concept which seems very much open to question and it seems that further work is required on this. DISCUSSION Lejeune, Gautier, Lafourcade, Berger, and Polani (1969) refers to the incidence of this con- Turpin (1964a) found a left cerebellar hemisphere dition as being between 1 in 50,000 to 1 in that was smaller than its fellow. Crome and Stern J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from 718 Jack Colover, Mary Lucas, J. A. Comley, and A. M. Roe

(1967) in their case described absence of the ter, and Baitsch (1965) had a patient who also olfactory nerves with small optic nerves and showed nystagmus-Hirschhorn et al. (1965) also optic chiasm. The central parts of the olfactory found absence of the septum pellucidum. The brain were absent and there was arrhinencephaly. child described by Cavalieri et al. (1964) showed Clinically most of the patients show hypotonia pachygyria. of the limbs. A small number of cases have mani- Clinically, there is a great variation in the fested spasticity. This was recorded by Milunsky severity of the physical abnormalities and the and Chitham (1966). Dumars, Gaskill, and Kitz- degree of mental retardation. The karyotypes miller (1964) described a child with spastic also show differences in the amount of chromo- quadriparesis. A spastic shuffling gait occurred some material deleted. It is tempting, in view of in the patient recorded by Bergman, Flodstrom, the small deletion and the mildness of the abnor- and Ansehn (1965). Spasm ofthe thigh adductors mality present, to try and relate the size of the was found by McGavin et al. (1967). Of 18 cases deletion to the degree ofabnormality. But it must reviewed by Berg et al. (1965) 12 were hypotonic be remembered that different segments of the and two were spastic. chromosome may be lost in each case. Laurent and Robert (1966) collected three As no abnormality could be detected in the brothers with this condition, which was unusual parents of the proband this chromosomal dele- as being prevalent in one particular family, and tion arose either during gametogenesis in one they all had extensor plantar reflexes and brisk parent or in the very early zygote. It is generally tendon reflexes. De Grouchy et al. (1964) and accepted that terminal deletions do not occur in Hustinx and Wijffels (1965) described extensor man, so that it is necessary to postulate two plantar responses also. Our patient showed a breaks and rejoining of the chromosome with unilateral extensor plantar response. loss of the interstitial part. Therefore, it is notProtected by copyright. In the series of 50 cases reviewed by McGavin possible to know which part of the chromosome et al. (1967) five had convulsions. Solitare's has been lost. (1967) patient had convulsions until the age of 4 The value of chromosome studies in such years. Hirschhorn, Cooper, and Firschein (1965) patients is twofold. They show a cause for the described a patient who showed as many as 20 abnormalities so that other investigations into myoclonic seizures a day and who subsequently the reasons for the mental retardation need not died in a seizure. One of the patients recorded by be undertaken; and, if the karyotype of the Lejeune et al. (1964b) developed coma and hemi- parents is normal, they can be given a good plegia as a result of complications due to con- prognosis for future pregnancies. genital heart disease. Petit mal was present in a Although the disease is rare, the literature cited patient described by De Capoa, Warburton, indicates that a number ofthe children born with Breg, Miller, and Miller (1967). this condition survive childhood and that they Tremors or tremulousness have been described may be seen by neurologists dealing with young by Turner et al. (1966) and Cavalieri, Mastella, adults. It is hoped that the detailed description and Tiepolo (1964). Laurent and Robert (1966) of this case may enable other similar patients tohttp://jnnp.bmj.com/ referred to one patient who not only had jerki- be recognized. ness of arm movements but synkinesia of the upper limbs. It is considered that the hypotonia We would like to thank Editions Delachaux and shown by most patients could be of cerebellar Niestle, Neuchatel, Switzerland, for their kindness in origin and the cerebellar signs shown by our allowing us to reproduce Fig. 5 from the Manuel patient would also fit into this category. Berg et Pour L'Examen Psychologique de L'Enfant, by R. Zazzo. al. (1965) described a waddling gait. Unilateral on September 28, 2021 by guest. optic atrophy was present in a case recorded by Lejeune et al. (1964b). REFERENCES Air studies have only been carried out in a few Abercrombie, M. L. J. (1964). Perceptual and Visuo-Motor cases. Dilatation of the lateral ventricles was Disorders in Cerebral Palsy, pp. 10-16. Heinemann: found London. by Lejeune et al. (1964b) and Hustinx and Berg, J. M., Delhanty, J. D. A., Faunch, J. A., and Ridler, Wijffels (1965). Wolf, Reinwein, Porsch, Schro- M. A. C. (1965). Partial deletion of short arm of a chromo- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.711 on 1 October 1972. Downloaded from Neurological abnormalities in the 'cri-du-chat' syndrome 719

some of the 4-5 group (Denver) in an adult male. Jouirnal Lejeune, J., Lafourcade, J., Berger, R., and Rethore, M.-O. of Mental Deficiency Research, 9, 219-228. (1965). Malade du cri du chat et sa reciproque. Annales de Bergman, S., Flodstrom, I., and Ansehn, S. (1965). Cri du Genet&ique, 8, 11-15. chat. Lancet, 1, 768-769. McCracken, J. S., and Gordon, R. R. (1965). 'Cri du chat' Cavalieri, S., Mastella, G., and Tiepolo, L. (1964). La sin- syndrome. A new clinical and cytogenetic entity. Lancet, 1, drome della voce da gatto. Fracastoro, 57, 369-381. 23-25. Crome, L., and Stern, J. (1967). The Pathology of Mental McGavin, D. D. M., Cant, J. S., Ferguson-Smith, M. A., and Retardation, pp. 107-108. Churchill: London. Ellis, P. M. (1967). Cri-du-chat syndrome with an appar- De Capoa, A., Warburton, D., Breg, W. R., Miller, D. A., ently normal karyotype. Lancet, 2, 326-330. and Miller, 0. J. (1967). Translocation heterozygosis: a Miller, 0. J., Breg, W. R., Warburton, D., Miller, D. A., cause of five cases of the cri du chat syndrome and two Firschein, I. L., and Hirschhorn, K. (1966). Alternative cases with a duplication of chromosome number five in DNA replication patterns associated with long arm length three families. American Journal of Human Genetics, 19, of chromosomes 4 and 5 in the cri du chat syndrome. 586-603. Cytogenetics, 5, 137-151. De Grouchy, J., Arthus, M., Salmon, Ch., Lamy, M., and Miller, 0. J., Warburton, D., and Breg, W. R. (1969). Thieffry, S. (1964). Le syndrome du cri du chat. Une nou- Deletions of group B chromosomes. Birth Defects, 5, velle observation. Annales de Ginftique, 7, 13-16. No. 5, 100-105. Dumars, K. W. Jr., Gaskill, C., and Kitzmiller, N. (1964). Le Milunsky, A., and Chitham, R. G. (1966). The cri du chat cri du chat (crying cat) syndrome. American Journal of syndrome. Jouirnal of Mental Deficiency Research, 10, Diseases in Childhood, 108, 533-537. 153-157. Dyggve, H. V., and Mikkelsen, M. (1965). 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